Developmental trajectories of neuroanatomical alterations associated with the 16p11.2 Copy Number Variations

Alonso Cárdenas-de-la-Parra, Sandra Martin-Brevet, Clara Moreau, Borja Rodriguez-Herreros, Vladimir S. Fonov, Anne M. Maillard, Nicole R. Zürcher, Addor Marie-Claude, Andrieux Joris, Arveiler Benoît, Baujat Geneviève, Sloan Béna Frédérique, Belfiore Marco, Bonneau Dominique, Bouquillon Sonia, Boute Odile, Brusco Alfredo, Busa Tiffany, Caberg Jean-Hubert, Campion DominiqueColombert Vanessa, Cordier Marie-Pierre, David Albert, Debray François-Guillaume, Delrue Marie-Ange, Doco Fenzy Martine, Ulrike Dunkhase Heinl (Member of author group), Edery Patrick, Christina Fagerberg (Member of author group), Faivre Laurence, Forzano Francesca, Genevieve David, Gérard Marion, Giachino Daniela, Guichet Agnès, Guillin Olivier, Héron Delphine, Isidor Bertrand, Jacquette Aurélia, Jaillard Sylvie, Journel Hubert, Keren Boris, Lacombe Didier, Lebon Sébastien, Le Caignec Cédric, Lemaître Marie-Pierre, Lespinasse James, Mathieu Dramart Michèle, Mercier Sandra, Mignot Cyril, Kristina Pilekær Sørensen (Member of author group), Britta Schlott Kristiansen (Member of author group), 16p11.2 European Consortium

Research output: Contribution to journalJournal articleResearchpeer-review


Most of human genome is present in two copies (maternal and paternal). However, segments of the genome can be deleted or duplicated, and many of these genomic variations (known as Copy Number Variants) are associated with psychiatric disorders. 16p11.2 copy number variants (breakpoint 4–5) confer high risk for neurodevelopmental disorders and are associated with structural brain alterations of large effect-size. Methods used in previous studies were unable to investigate the onset of these alterations and whether they evolve with age. In this study, we aim at characterizing age-related effects of 16p11.2 copy number variants by analyzing a group with a broad age range including younger individuals. A large normative developmental dataset was used to accurately adjust for effects of age. We normalized volumes of segmented brain regions as well as volumes of each voxel defined by tensor-based morphometry. Results show that the total intracranial volumes, the global gray and white matter volumes are respectively higher and lower in deletion and duplication carriers compared to control subjects at 4.5 years of age. These differences remain stable through childhood, adolescence and adulthood until 23 years of age (range: 0.5 to 1.0 Z-score). Voxel-based results are consistent with previous findings in 16p11.2 copy number variant carriers, including increased volume in the calcarine cortex and insula in deletions, compared to controls, with an inverse effect in duplication carriers (1.0 Z-score). All large effect-size voxel-based differences are present at 4.5 years and seem to remain stable until the age of 23. Our results highlight the stability of a neuroimaging endophenotype over 2 decades during which neurodevelopmental symptoms evolve at a rapid pace.

Original languageEnglish
Article number116155
Number of pages7
Publication statusPublished - Dec 2019


  • 16p11.2 Copy number variants
  • Brain development
  • Genetics
  • Imaging
  • Neurodevelopmental disorders
  • Normative growth trajectories


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